In contemporary society, prolonged sitting has been incorporated into our lives across many settings, including transportation, the workplace, and the home. New evidence indicates that too much sitting (also known as sedentary behavior—which involves very low energy expenditure, such as television viewing and desk-bound work) is adversely associated with health outcomes, including cardio-metabolic risk biomarkers, type 2 diabetes and premature mortality. Importantly, these detrimental associations remain even after accounting for time spent in leisure time physical activity. Epidemiological and experimental studies make a persuasive case that too much sitting should now be considered an important stand-alone component of the physical activity and health equation, particularly in relation to diabetes and cardiovascular risk.
Such risk might be confounded by eating precooked/canned food and snacks, because it is known that this type of food is frequently consumed while watching TV. In fact, there is evidence that it is the type and amount of food consumed while viewing TV that is responsible for the association between TV viewing and excess weight that are associated with low physical activity. Snacking has been associated with an additional 1.5 h/week of TV viewing compared with not snacking in adults. Snacking is associated with poorer diet quality as linked to a higher intake of total energy, total fat, animal and vegetable fat and to a greater consumption of fast-foods, sweets, and sugar-sweetened beverages. The mechanisms of some of the observed associations are easy to guess. For instance, eating while watching TV or eating while seated on a sofa or an armchair could naturally be associated with more time watching TV. This is also the case for eating precooked/canned food and snacks, because it is known that this type of food is frequently consumed while watching TV. In fact, there is evidence that it is the type and amount of food consumed while viewing TV that is responsible for the association between TV viewing and excess weight.
Most US residents lead sedentary lives and do not get enough physical activity. In the USA, less than 5% of adults and only 8% of adolescents (aged 12-19 years) adhere to the recommendation for 30 and 60 min, respectively, of daily physical activity. The amount of time spent doing sedentary activities, like sitting at a computer or watching TV, has also increased dramatically. Now, 8-18-year olds in the USA devote an average of 7 h and 38 min to using entertainment media across a typical day, which translates to 53 h a week.
Higher amounts of overall sitting time and television viewing are positively associated with mortality. In the NIH-AARP Diet and Health Study, 240,819 adults (aged 50-71 y) who did not report any cancer, cardiovascular disease, or respiratory disease at baseline were examined. Mortality was ascertained over 8.5 y. Sedentary behaviors were positively associated with mortality after adjustment for age, sex, education, smoking, diet, race, and moderately vigorous physical activity (MVPA).
Sitting is unhealthy. Both longer lengths and fewer breaks from sitting time increase metabolic risk and transitioning to a greater sedentary time for one day reduced insulin sensitivity significantly. Reduction in daily ambulatory activity increased insulin response to an oral glucose tolerance test and visceral fat mass at 1 and 2 weeks, respectively.
The natural history of diabetes type 2 (T2D) is associated with progressive deterioration in insulin sensitivity (insulin resistance) that is initially compensated for by an increase in insulin secretion (hyperinsulinemia) to maintain glycemic control. However, with time, β-cell function in the pancreas deteriorates and insulin is no longer secreted in appropriate amounts to compensate for low insulin sensitivity leading to glucose intolerance, hyperglycemia and the subsequent diagnosis of T2D. Diabetes is associated with fatty liver disease, cognitive decline and some cancers, and, end-stage complications include blindness, renal failure, amputation and cardiovascular disease. Persons with T2D have approximately a twofold increased mortality rate and the associated costs put a huge economic burden on health care systems. In the U.S., one-third of adults and 16-18% of youth are obese, up from 5 to 6% three decades ago. Increases in rates of type 2 diabetes have closely tracked increases in obesity. In the U.S., diabetes affects 8.3% of the population that includes 18.8 million with diagnosed diabetes and another 7 million undiagnosed. An additional 35% of U.S. adults or 79 million Americans aged equal or greater than 20 years have pre-diabetes and about one in three American adults will have diabetes by the year 2050.
The diabetes epidemic has become global. An estimated 500 million people worldwide are obese and another 1.5 billion are overweight. About 3 million people die each year due to overweight and obesity. In 2011, 366 million people worldwide had diabetes and it caused 4.6 million deaths. The International Diabetes Federation estimates that by 2030, the number of individuals with diabetes will rise by almost 43% to 552 million. In 2011, about 280 million people had pre-diabetes; by 2030 this number is expected to rise to nearly 400 million. Therefore, determining effective prevention and treatment strategies are essential.
The clinical significance of inactivity-induced decrease in insulin sensitivity is that the presence of decreased insulin sensitivity is necessary to develop pre-diabetes, in turn a precursor to T2D. Individuals with T2D have shorter average life span. Not surprisingly, lifetime physical inactivity is associated with increased T2D prevalence and mortality. Furthermore, glucose metabolism becomes dysfunctional prior to changes in body fat content and/or VO2max suggesting that this malady likely is inactivity-induced rather than whole body adiposity induced.
Accumulating evidence suggests that obtaining the recommended volume of exercise per week does not necessarily protect an individual from disease. For example, office workers who achieve 150 min of defined exercise per week but remain grossly sedentary in every other facet of their life, including sitting for >8 h/day, have an elevated risk of all-cause mortality. Unfortunately, the average adult spends 50-60% of their day in sedentary pursuits defined as sitting or lying and less than 3% of US adults obtain the suggested levels of weekly physical activity. So in most cases individuals are both sedentary and inactive. But, moving beyond these important classifications, what is the current evidence to support that ‘type 2 diabetes sits in a chair’? Adolescents with T2D spent 56 more minutes per day being sedentary than their age-matched non-diabetic controls. Sitting time was also inversely associated with glycaemia even when correcting for physical activity. Television watching time can be used as a strong surrogate of sitting or sedentary time. Television watching time >40 vs. <1 h a week increases the risk of developing T2D by 50-70%. The link between television watching time (a surrogate of sitting time) and risk of T2D is not substantially altered when correcting for daily physical activity. Even if an individual has increased physical activity levels they are still at risk if sedentary behavior is not corrected. In adults at high risk of T2D, time spent sedentary is strongly and adversely associated with 2-h OGTT glucose levels.7
Besides the work place, commuting must be considered as part of the day in which sitting time occurs. The 2009 US Census Bureau reported that of 132 million people surveyed, only 3.8 million people commuted to work using non-vehicular means of transport (walking and cycling). Thus 97% of the US population sits in a vehicle to and from the workplace every day. Since the average commute time is 25.1 min, the average US citizen spends approximately 50 min/day sitting in a vehicle to get to and from work. If active travel such as walking or cycling the entire distance is not feasible, to easily reduce this sitting time one may park their car or dismount the bus/train further from work and walk the remaining distance. Alternatively, one might choose to stand rather than sit on their bus/train journey to the workplace. But compliance on this issue is difficult to attain.
Epidemiologic investigations into the health effects of a “sedentary lifestyle” has customarily focused on the adverse effects associated with a lack of participation in recommended levels of exercise, or moderate-vigorous physical activity (MVPA). Understanding of the potential adverse effects of time spent in sedentary behaviors on overall physical activity levels is evolving rapidly as the role of daily activities and non-exercise energy expenditure in health is better defined. Time spent in sedentary behaviors reflects a wide range of human pursuits that involve sitting or reclining and only low levels of energy expenditure. The average US adult spends more than half of his or her waking day in sedentary behaviors, and older adults spend upward of 60%, or 9 h, of their time each day in sedentary behaviors. Higher amounts of sedentary time are independently associated with increased risk of weight gain and obesity, poor metabolic health, and mortality. Sitting during leisure time was positively associated with mortality even after overall physical activity levels were controlled for, and that high levels of total activity did not minimize risk related to sitting. Similar findings on the independent and combined effects of activity and overall sitting time and television viewing have been found.
The estimated gains of life expectancy in the U.S. population are 2 years for reducing excessive sitting to <3 hours per day and a gain of 1.4 years for reducing excessive television viewing to 2 hours per day. van der Ploeg H P, Chey T, Korda R J et al., “Sitting time and all-cause mortality risk in 222 497 Australian adults,” Arch Intern Med 2012; 172(6):494-500, linked prospective questionnaire data from 222 497 individuals 45 years or older from the 45 and Up Study to mortality data from the New South Wales Registry of Births, Deaths, and Marriages (Australia) from Feb. 1, 2006, through Dec. 31, 2010. In 621 695 person-years follow-up with a mean of 2.8 years), 5405 deaths occurred. All-cause mortality hazard ratios were 1.02 (95% CI, 0.95-1.09), 1.15 (1.06-1.25), and 1.40 (1.27-1.55) for 4 to less than 8, 8 to less than 11, and 11 or more hours per day of sitting, respectively, compared with less than 4 h/d, adjusting for physical activity and other confounders.
The population-attributable fraction for sitting was 6.9%. The association between sitting and all-cause mortality appeared consistent across the sexes, age groups, body mass index categories, and physical activity levels and across healthy participants compared with participants with preexisting cardiovascular disease or diabetes mellitus. Therefore, prolonged sitting is a risk factor for all-cause mortality, independent of physical activity.
In individuals older than 60 years, every additional hour a day spent sitting is linked to a 50 percent greater risk of being disabled—regardless of how much participation in moderate exercise. Thus, sedentary behavior is its own risk factor for disability, separate from lack of moderate vigorous physical activity. Sedentary behavior is almost as strong a risk factor for disability as lack of moderate exercise. Disability that affects more than 56 million Americans is the inability to carry out daily activities of living such as eating, dressing or bathing oneself, getting in and out of bed and walking across a room. Disability increases the risk of hospitalization and institutionalization and is a leading source of health care costs, accounting for $1 in $4 spent.
It has been recommended that one should achieve 10,000 steps per day as measured with a pedometer or accelerometer which represents 30 min of moderate-to-vigorous physical activity (MVPA) added to a minimum level of baseline physical activity. Thirty minutes of moderate activity translates to 3,000-4,000 steps at a stepping rate of 100 steps per minute. Adding this amount to the questionable assumption of 6,000-7,000 steps from routine activities of daily living approximates 10,000 steps per day. However, a recent study, Scheers T, Philippaerts R, Lefevre J. “Compliance with different physical activity recommendations and its association with socio-demographic characteristics using an objective measure,” BMC Public Health 2013; 13:136, revealed that only 16% men and 14% of women reached at least 10,000 steps per day on seven consecutive days. When the frequency requirement was decreased to 5 days/week, 45% of men and 55% of women achieved this goal.
In a study of sedentary office workers monitored with a pedometer for step counts had significantly higher levels of sedentary behavior on work days (517±144 min/day) compared with non-work days (339±137 min/day). Overall, 65% of time at work was sedentary, and sitting at work accounted for 63% of total daily sitting time. Those who were most sedentary at work did not compensate by reducing their sedentary behavior outside work. In fact, those who reported sitting for longest at work reported sitting for longer outside work. The conclusion of this study was that occupational health interventions should aim to reduce workplace and leisure-time sitting in sedentary office workers.
This background of the health hazards of excessive sitting clearly indicates need for an intervention to counteract its ill effects. In an advanced society, recommendations for alterations in life style such as intermittently changing posture to standing have been poorly accepted. The basis for the adverse effects of prolonged sitting must be understood in order to arrive at a solution. Since the major mortality outcomes of prolonged sitting relate to development of cardiovascular disease and diabetes, one must look to the commonality between these two diseases and their pathophysiologic basis. This lies in observations that a sedentary life style leads to 1) reduced energy expenditure with the potential development of obesity that is compounded by obesity-related eating behaviors and 2) endothelial dysfunction that is the basis in whole or in part for most chronic “sitting” diseases.
A recent attempt to provide a solution for too much sitting has been to incorporate a “treadmill desk” into the office or home. An internet site: http://www.workwhilewalking.com/how-many-treadmill-desks-are-in-use-today estimated that from 300,000 to 500,000 were either purchased or constructed in the United States as of the fourth quarter 2013. The average price for this equipment is $2,400 which also requires an accompanying desk for sitting and a large amount of floor space and non-portability.
The speed for walking on a treadmill while working at a computer is less than 2 miles per hour. To prevent injury, treadmill desks require compliance with the same ergonomic safety standards recommended for any computer desk, including placement such that the user's wrists are flat by the keyboard, their elbows form a 90-degree angle when typing, and their eyes may look forward to the monitor. Users who tested treadmill desks reported advice to retain a traditional desk with a seat and to alternate between sitting and walking at different desks while becoming accustomed to the treadmill desk. Additionally, reading email and surfing the Internet were found to be easier to manage than learning to type or write while standing and walking which is a multitasking procedure. Talking on the phone while walking can be disruptive in some cases either because of changing the breathing rate of the user or because of the noise from the treadmill itself.
A treadmill desk is not intended to provide aerobic exercise but to set the user's metabolism over the basal metabolic rate, e.g. to increase non-exercise activity thermogenesis (NEAT). In this respect, treadmill desks do not address the other major problem of excessive sitting, the development of endothelial dysfunction.
While the health advantages of sitting less are well established, helping to cut the risk of obesity and heart disease, the productivity benefits of so-called active workstations are less clear from the results of the small studies to date. A 2011 Mayo Clinic study of 11 medical transcriptionists found that typing speed and accuracy slowed by 16% while walking on a treadmill desk compared with sitting. And a 2009 study from the University of Tennessee, with 20 participants, found that treadmill walking resulted in an up to 11% deterioration in fine motor skills like mouse clicking, and dragging and dropping, as well in as cognitive functions like math-problem. Thus, the treadmill desk offers a way to reduce sedentariness in the workplace and has potential to reduce employee obesity and health care costs. However, more than 4 hours of training will be necessary to prevent a significant drop in employee productivity.
Endothelial dysfunction occurs when cells lining the inner wall of blood vessels exposed to flowing blood 1) fail to release beneficial mediators into the circulation, 2) release diminished amounts of beneficial mediators into the circulation, and/or 3) release deleterious substances into the circulation. The underlying basis for endothelial dysfunction is reduced shear stress to the inner lining of blood vessels (endothelium) from blood flowing slowly or oscillating to and fro over it.
Endothelial dysfunction is caused by chronic exposure to various stressors such as oxidative stress and inflammation resulting in impaired endothelial nitric oxide bioavailability. Biomechanical forces on the endothelium, including low and oscillatory shear stress associated with hypertension and arteriosclerosis are also important causes of endothelial dysfunction. Smoking increases oxidative stress and is a major risk to endothelial dysfunction. In patients with diabetes, insulin resistance and signaling is impaired. Increased vascular inflammation, including enhanced expression of interleukin-6 (IL-6), vascular cellular adhesion molecule-1 (VCAM-1) and monocyte chemoattractant protein (MCP-1) are observed, as is a marked decrease in NO bioavailability. Furthermore, hyperglycemia leads to increased formation of advanced glycation end products (AGE) that quench NO and impair endothelial function. Patients with diabetes invariably show an impairment of endothelium-dependent vasodilation, a marker of endothelium dysfunction. Therefore, understanding and treating endothelial dysfunction is a major focus in the prevention of vascular complications associated with all forms of diabetes mellitus.
Because the hallmark of endothelial dysfunction is reduced bioavailability of nitric oxide, oral administration of L-arginine, the substrate for generation of NO by endothelial nitric oxide, have been attempted but met with failure. Oral administration of L-arginine is met with increasing levels of arginase that produce deleterious free oxygen radicals. Increased activity of arginase in endothelial dysfunction due to low or oscillatory shear stress is present in hypertension, pulmonary arterial hypertension, atherosclerosis, myocardial ischemia, congestive heart failure, and diabetes mellitus. Elevated levels of arginases cause eNOS uncoupling in that eNOS reaction with L-arginine produces superoxide instead of nitric oxide which results in vascular oxidative stress and inflammatory responses. Increased laminar and pulsatile shear stress to the endothelium during exercise or WBPA inhibits release of arginases thereby improving endothelial dysfunction.
Normal or elevated shear stress mechanically stimulates the endothelial cells to increase the activity of genes responsible for release of beneficial mediators, the most important one of which is nitric oxide. Its discovery led to a Nobel Prize in Medicine for Robert F. Furchgott, Louis J. Ignarro, and Ferid Murad in 1998. Two processes increase shear stress, one designated laminar shear stress and the other pulsatile shear stress, both of which take place during exercise.
Laminar shear stress occurs when blood flow increases over the endothelial surface which in turn mechanically distorts and realigns individual cells making this layer in contact with the blood stream. Pulsatile shear stress (PSS) occurs during the normal state of pulsatile blood flow as a function of heart rate that increases with exercise. It can also be increased by addition of pulses via a pulsatile pump over a steady flow pump in an in-vitro isolated perfused, blood vessel preparation where increased amounts of nitric oxide are detected. Palatini P, Mos L, Mormino P et al., “Blood pressure changes during running in humans: the ‘beat’ phenomenon,” J Appl Physiol 1989; 67(1):52-59, showed that during running, each time the foot strikes the ground, a pulse is added to the circulation that is superimposed upon the body's own pulses and is detected in the radial arterial pressure waveform. In athletes, during warm-up, stride frequency ranges from 130-165/min, during submaximal speed, from 140-175/min, and during sprinting from 165-205/min. The addition of pulses during locomotion as well a whole body periodic acceleration increases pulsatile shear stress.
Normal vascular endothelial function is essential for maintenance of vascular health vasomotor control of both conduit and resistance vessels. These functions are due to the production of numerous autacoids, of which nitric oxide (NO) has been the most widely studied and important. Exercise training has been shown, in many animal and human studies, to augment endothelial, NO-dependent vasodilatation in both large and small vessels.
The extent of the improvement in humans depends upon the muscle mass subjected to training; with forearm exercise, changes are restricted to the forearm vessels while lower body training can induce generalized benefit. Increased NO bioactivity with exercise training has been readily and consistently demonstrated in subjects with cardiovascular disease and risk factors, in whom antecedent endothelial dysfunction exists. These conditions may all be associated with increased oxygen free radicals which impact on NO synthase activity and with which NO reacts; repeated exercise and shear stress stimulation of NO bioactivity redresses this radical imbalance, hence leading to greater potential for autacoid bioavailability.
Human studies indicate that exercise training improves endothelial function by up-regulating endothelial nitric oxide synthase (eNOS) protein expression and its active phosphorylated form that acts upon circulating L-Arginine to produce nitric oxide. While the increase in NO bioactivity dissipates within weeks of training cessation, studies indicate that if exercise is maintained, the short-term functional adaptation is succeeded by NO-dependent structural changes, leading to arterial remodeling and structural normalization of shear.
Today, most jobs and leisure time activities involve hours of continuous sitting. The underlying nature of sitting does not promote muscular contractions, augmented energy expenditure, or increased blood flow. Sitting also changes the angle at which major arteries (femoral and popliteal) run; as compared to a standing or supine posture. Bends within the arterial tree alter flow patterns which have been shown to affect the atherosclerotic process. Due to the predominantly seated posture during sedentary activity, turbulent blood flow might be augmented in deformed arterial segments of the lower extremities. The turbulent flow may also be an underlying mechanism for the prevalence of atherosclerosis in the femoral-popliteal arterial segment. Additionally, shear rate (estimate of shear stress without accounting for blood viscosity) is lower in the femoral artery versus the brachial artery in the supine, standing, and seated positions. Perhaps repeated sedentary activity presents a chronic stimulus in the lower extremity which promotes the development of atherosclerosis. In the seated posture, blood pools in the leg, and both peripheral resistance and blood pressure in the leg increase. Sitting upright produces low mean shear stress in the legs as compared to the supine position, which over time may influence endothelial function. Low mean shear stress due to sedentary activity elevates oxidative stress that promotes atherogenesis. Low shear stress decreases endothelial nitric oxide synthase (eNOS) expression which leads to decreased bioavailability of nitric oxide and oxidative stress Along these lines, Thosar S S, Johnson B D, Johnston J D et al., “Sitting and endothelial dysfunction: the role of shear stress.” Med Sci Monit 2012; 18(12):RA173-RA180 showed that sedentary mice have an increased superoxide production. In this study, inactivity promoted NADPH oxidase activity leading to increased oxidative stress.
Along these lines, oscillatory flow or low shear stress promotes atherosclerosis (atheroprone), endothelial dysfunction and inflammation that can be combated by exercise by exercise or by anything that introduces additional pulses into the circulation such as whole body periodic acceleration. The latter adds pulses as a function of the frequency of repetitively moving a supine subject on a motorized platform head to foot to and fro about 100 to 180 times a minute. As the body is repetitively accelerated and decelerated, small pulses are added to the circulation which are superimposed upon the normal pulse. This increases pulsatile shear stress that activates a host of endothelial genes of which stimulation of endothelial nitric oxide synthase to increase release of nanomolar amounts of nitric oxide into the circulation is among the most important of this effect.
Pulsatile (PSS) and laminar shear stress (LSS) during exercise or in the case of PSS whole body periodic acceleration (WBPA) cause the release of beneficial mediators: 1) vasodilators—nitric oxide (NO), prostacyclin, endothelium derived hyperpolarizing factor, adrenomedullin, C-natruretic peptide, SIRT1, BH4; 2) antiproliferative—NO, prostacyclin, transforming growth factor-β, heparin; 3) antithrombotic—NO, prostacyclin, tissue plasminogen activator (tPA), protein C, tissue factor inhibitor, 3) angiogenesis—vascular endothelial growth factor (VEGF).
Potentially deleterious substances released from the endothelium during low or oscillatory shear stress include: 1) vasoconstrictors—endothelin-1, angiotensin-II, thromboxane A2, oxygen free radicals, prostaglandin H2; 2) pro-proliferative—endothelin-1, angiotensin-II, free oxygen radicals, platelet-derived growth factor, basis fibroblast growth factor, insulin-like growth factor, arginases; 3) prothrombotic—endothelin-1, free oxygen radicals, plasminogen inhibitor-1, thromboxane A2, fibrinogen, tissue factor; 4) inflammatory markers—cell adhesion molecules (P- and E-selectin, ICAM, VCAM), chemokines, nuclear factor kappa beta (NF-κβ) and STAT3.
In addition to the direct activity of these substances, many have signaling activity for other substances. For example, pulsatile and laminar shear stress that increase endothelial derived NO which in turn may increases brain derived neurotrophic factor (BDNF) and glial derived neurotrophic factor (GDNF) as well as SIRT1 in brain and muscle. In addition to the increased activity of endothelial nitric oxide synthase (eNOS) in the endothelium, PSS increases eNOS in the myocardium and neuronal nitric oxide synthase (nNOS) in heart and skeletal muscle. Nitric oxide released from activation of eNOS promotes release of endothelial progenitor cells and stem cells from the bone marrow into the circulation, a necessity for neovascularization.
Pulsatile shear stress (PSS) increases Kruppel-Like Factor-2 (KLF2) that is necessary for up-regulation of eNOS & thrombomodulin, activates SIRT1 that acts to prevent vascular cellular senescence, dysfunction and atherosclerosis and upregulates GTPCH I, the rate-limiting enzyme of BH4 biosynthesis, favoring NO over superoxide generation by eNOS thereby preventing and treating eNOS uncoupling. All these actions promote a healthy endothelium and improve endothelial dysfunction.
Williams C B, Gurd B J, “Skeletal muscle SIRT1 and the genetics of metabolic health: therapeutic activation by pharmaceuticals and exercise,” Appl Clin Genet 2012; 5:81-91, provides interesting insights into the place of exercise, with beneficial mediator activation due to increased laminar and shear stress as is also the case with WBPA, in management of obesity and metabolic disease, exercise has several inherent advantages over pharmaceutical intervention.
First, the improved metabolic function associated with exercise comes at minimal financial cost, while a pharmaceutical intervention carries a substantial financial commitment from both the individual and healthcare provider. Second, in addition to improved skeletal muscle mitochondrial function and metabolic/cardiovascular health, regular exercise is associated with a myriad of beneficial effects ranging from the prevention and treatment of mental disorders and cancer to alleviating symptoms and improving quality of life in many chronic diseases. Third, exercise is implicated in a systemic improvement of health with little to no risk of adverse side effects. Pharmaceuticals are often associated with undesirable side effects, and are inherently designed to be specific, eliminating the possibility of a systemic health improvement. Finally, there is evidence that exercise, as part of a lifestyle intervention, induces superior improvements compared to pharmaceutical intervention in subjects with metabolic disease. In light of these arguments, it makes both health and financial sense that exercise becomes a first-line tool in both the prevention and treatment of obesity and obesity-related disease
Beneficial mediators such as NO derived from eNOS and others can counteract inflammatory mediators. For example, increased PSS produced by WBPA stimulates activity of eNOS to increase NO that blunts the late inflammatory response in allergic bronchial asthma through inhibition of nuclear factor kappa beta. NO is the most important beneficial mediator released by PSS; its actions are listed below.
Vasodilator: acts on vascular smooth muscle to increase cGMP (improves organ blood flow with substantial increases in cerebral blood flow and myocardial microvascular blood flow).
Anti-atherosclerotic: prevents adhesion of leukocytes & platelets to endothelium that cause endothelium dysfunction; prevents adhesion of leucocytes and platelets to endothelium that cause injury.
Anti-inflammatory: inhibits NF-κβ, STAT3, and inflammatory cytokines that together with free oxygen radicals (ROS) are responsible for pathogenesis of many chronic diseases.
Anticytokines: suppresses TNF-α and IL-1.
Antichemokines: downregulates MIP-1 and MIP-2.
Antiapoptotic: downregulates p53, inhibits human caspases, induces expressions of heat shock proteins.
Reduces oxidative stress: scavenges ROS and RNS; inhibits NADPH oxidase activity.
Anti-tumorigenic: inhibits NF-κβ activity and other protumorigenic genes.
Organ preconditioning, conditioning & postconditioning: minimizes deleterious effects of ischemia to heart, brain, gut, lungs, liver, kidneys and skeletal muscles.
Anti-diabetogenic: promotes glucose uptake by cardiac and skeletal muscles as well as adipose tissues; combats microvascular complications.
Modulates corticostriatal plasticity: strengthens interconnections at neural synapses thereby relieving movement, learning, & fatigue disorders in neurological diseases.
Minimizes cognitive decline with ageing.
Reverses ventricular remodeling.
Promotes wound & bone fracture healing.
Mobilizes endothelial progenitor cells (EPCs) from bone marrow: for vascular repair.
Signals increase of Brain and Glial Derived Neurotrophic Factors (BDNF & GDNF) and SIRT1.
Pulsatile Shear Stress and Diabetes
With respect to Type 2 diabetes associated with a sedentary life style, increased pulsatile shear stress as delivered by whole body periodic acceleration (WBPA) has immediate effects. Thus, 8 patients with T2D were studied before and immediately after a single session of 45-min session of WBPA for changes of coronary flow reserve (CFR), a measure of the capacity of myocardial microcirculation as well as their diabetic status. WBPA increased CFR from 2.3±0.3 to 2.6±0.4 (p=0.02). WBPA decreased serum insulin level from 26±19 IU/ml to 19±15 IU/ml (p=0.01) and increased total adiponectin from 11.6±7.3 g/ml to 12.5±8.0 g/ml (p=0.02) and high molecular weight adiponectin from 4.9±3.6 g/ml to 5.3±3.9 g/ml (p=0.03), whereas the serum glucose level was stable from 207±66 mg/dl to 203±56 mg/dl (p=0.8). This study demonstrates that a single session of WBPA treatment simultaneously improved coronary microcirculation and glucose tolerance in patients with T2D. Increased pulsatile shear stress delivered with WBPA was assessed on blood flow recovery in a mouse model of hindlimb ischemia and in patients with peripheral arterial disease. After unilateral femoral artery excision, mice were assigned to either the WBPA (n=15) or the control (n=13) group. WBPA was applied at 150 cpm for 45 minutes under anesthesia once a day. WBPA significantly increased blood flow recovery after ischemic surgery, as determined by laser Doppler perfusion imaging. Sections of ischemic adductor muscle stained with anti-CD31 antibody showed a significant increase in capillary density in WBPA mice compared with control mice. WBPA increased the phosphorylation of endothelial nitric oxide synthase (eNOS) in skeletal muscle. The proangiogenic effect of WBPA on ischemic limb was blunted in eNOS-deficient mice indicating that the stimulatory effects of WBPA on revascularization are eNOS dependent. Quantitative real-time polymerase chain reaction analysis showed significant increases in angiogenic growth factor expression in ischemic hindlimb by WBPA. Facilitated blood flow recovery was observed in a mouse model of diabetes despite there being no changes in glucose tolerance and insulin sensitivity. Furthermore, both a single session and 7-day repeated sessions of WBPA significantly improved blood flow in the lower extremity of patients with peripheral arterial disease. Thus, increased pulsatile shear stress increased blood supply to ischemic lower extremities through activation of eNOS signaling and upregulation of proangiogenic growth factor in ischemic skeletal muscle.
Diabetes is an important risk factor for the progression of Peripheral Arterial Disease (PAD). eNOS signaling plays an important role in endothelial dysfunction and vascular inflammation in the presence of insulin resistance. eNOS-dependent NO production is essential for the activation of insulin signaling. Therefore, increased shear stress through WBPA or aerobic exercise over the long term improves glucose tolerance and insulin sensitivity through phosphorylation of eNOS in heart and skeletal muscle as well as adipose tissue.
More recently, it has become apparent that SIRT1, which is increased by caloric restriction as well as pulsatile shear stress, is closely associated with lifespan elongation under CR. SIRT1 regulates glucose/lipid metabolism through its deacetylase activity on many substrates. SIRT1 in pancreatic β-cells positively regulates insulin secretion and protects cells from oxidative stress and inflammation, and has positive roles in the metabolic pathway via the modulation in insulin signaling. SIRT1 also regulates adiponectin secretion, inflammation, glucose production, oxidative stress, mitochondrial function, and circadian rhythms. Several SIRT1 activators, including resveratrol (present in small quantities in wine) have been demonstrated to have beneficial effects on glucose homeostasis and insulin sensitivity in animal models of insulin resistance.
MicroRNAs (miRs) in vascular endothelial cells play an essential role in shear stress-regulated endothelial responses. Atheroprotective pulsatile shear stress (PSS) induces miRs that inhibit mediators of oxidative stress and inflammation while promoting those involved in maintaining vascular homeostasis. Because multiple transcription factors are shear stress-inducible, a myriad of miRs can be induced or repressed by shear stress-inducible transcription factors. One of these transcription factors is Kruppel-Like Factor-2) (KLF2). This upregulates endothelial nitric oxide synthase (eNOS), thrombomodulin, and nuclear factor erythroid 2-related factor 2 that exert antiinflammatory, antithrombotic, and antioxidative effects in endothelial cells. Under PSS, the downregulation of adhesion molecule 1 (ICAM-1), VCAM-1, and E-selectin is likely to prevent the degradation of IκB and the consequent nuclear translocation of NF-κB p50 and p65 subunits. Both shear stress-sensitive miR-30b and miR-10a directly inhibit VCAM-1 and E-selectin. Additionally, the PSS—sensitive miR-181b inhibits the NF-κB pathway by directly targeting importin-α3 to decrease nuclear accumulation of p50 and p65 PSS is atheroprotective because it activates myocyte enhancer factor-5 (MEF5)/ERK5/MEF2 and AMP-activated protein kinase (AMPK) pathways, which merge at the transcriptional upregulation of KLF2. The beneficial anti-inflammatory effects and interactions with genes, cells and transcription factors have been aptly summarized by Marin and associates.
Laminar blood flow as well as caloric restriction increase SIRT1 level and activity, mitochondrial biogenesis, and expression of SIRT1-regulated genes in cultured endothelial cells (ECs). When the effects of different flow patterns are compared in vitro, SIRT1 level was significantly higher in ECs exposed to physiologically relevant pulsatile flow than oscillatory flow. Endothelial dysfunction (which is signified by increased oxidative and inflammatory responses) predisposes the arteries to atherosclerosis. Hence, SIRT1 activation by pulsatile flow may prevent EC dysfunction and counteract the risk factors associated with atherosclerosis. Compared with therapeutic interventions such as resveratrol (a substance in wine touted for its potential lengthening of life span), shear stress is more physiologically relevant to a direct effect on increasing SIRT1.
The application of laminar flow increases SIRT1 level and activity, mitochondrial biogenesis, and expression of SIRT1-regulated genes in cultured endothelial cells (ECs). When the effects of different flow patterns were compared in vitro, SIRT1 level was significantly higher in ECs exposed to physiologically relevant pulsatile flow than pathophysiologically relevant oscillatory flow. It is known that endothelial dysfunction (which is signified by increased oxidative and inflammatory responses) predisposes the arteries to atherosclerosis. Hence, SIRT1 activation by pulsatile flow may prevent EC dysfunction and counteract the risk factors associated with atherosclerosis. Compared with therapeutic interventions such as resveratrol and several small molecules developed for SIRT1 activation, shear stress is more physiologically relevant and pulsatile shear stress optimal.
SIRT1 plays an important role in maintaining neuronal health during aging. Hypothalamic functions that affect feeding behavior, endocrine function, and circadian rhythmicity are all regulated by SIRT1. Finally, SIRT1 plays protective roles in several neurodegenerative diseases including Alzheimer's, Parkinson's, and motor neuron diseases, which may relate to its functions in metabolism, stress resistance, and genomic stability.
Although the relevance of SIRT1 as a longevity gene has been disputed, its activation prevents diet-induced obesity and overexpression limits the risk of cancer and can thereby affect lifespan. As such, SIRT1 should be considered as a candidate for preventing and/or treating age-related diseases and for increasing healthspan. In fact, in contrast to increasing lifespan, which has limited medical relevance, improving healthspan has an immediate clinical and public health impact, given the ever increasing ‘greying’ of the world population.
Activation of SIRT1 has been observed in human skeletal muscle after 2 weeks and 6 weeks of exercise training. Consistent with these observations, exercise training improves oxidative capacity and fatty acid oxidation in skeletal muscle from obese adults, improves insulin sensitivity in obesity and type II diabetes, and decreases both risk factors for, and symptoms of, metabolic disease. In summary, exercise appears to activate the SIRT1/PGC-1α axis and improve skeletal muscle mitochondrial function and metabolic health. These results highlight the preventative and therapeutic potential of exercise for obesity and obesity-related disease.
Apparatuses are known that are intended to the solve problems relating to the sedentary lifestyle described above.
U.S. Pat. No. 4,862,875 to Heaton, Samuel discloses a leg exerciser for use by a person sitting in a chair. The device is located in front of the chair and the user puts his feet onto two boards which are at an acute angle to the horizontal. A mechanism, including a drive motor or flywheel inside the device, rocks the boards anti-phase about a horizontal axis lying transverse to the feet between acute angle positions. Sections of the boards lift out of and back into the planes of the boards during each cycle of rocking to lift and lower the user's toes relative to the remainder of the feet so that the feet are subjected to exercise movements similar to walking movements. The exerciser drives the leg blood pump with a view to improving the user's leg circulation. However, it does not supply useful mediators or pulsatile sheer stress.
U.S. Pat. No. 7,090,648 to Sackner, Marvin A. et al. relates to external addition of pulses to fluid channels of body to release or suppress endothelial mediators and to determine effectiveness of such intervention. A method of treatment is shown in which periodic acceleration is applied to the patient's fluid filled channels, thereby stimulating endothelial release of beneficial mediators and suppressing non-beneficial mediators. The periodic acceleration is provided by a reciprocating movement platform, which periodically accelerates the body, or a part thereof, in a headwards-footwards direction at a defined frequency.
One disclosed portion of this patent relates to a means for shifting the patient's legs up and down while the patient is seated, using an adjustable frequency, rotary motor mechanism that is cam adjustable for vertical displacement. While this relates to applying periodic acceleration of the legs, no mention is made of how it is accomplished.
U.S. Pat. No. 8,323,156, to Ozawa, Takahisa et al., relates to a piece of equipment that exercises the legs of a user without excessively straining the knee joint. However, the equipment is not configured to apply pulsatile stress to the patient's fluid filled channels.
Roberts V C, Sabri S, Pietroni M C et al., “Passive flexion and femoral vein flow: a study using a motorized foot mover,” Br Med J 1971; 3 (5766):78-81 describes a machine used to produce the controlled passive flexion of the foot (foot mover) is shown in the FIG. 12. The machine is intended for use on supine subjects, whether conscious or unconscious, and can be clamped to any operating table or bed as required. It consists essentially of a foot board which is pivoted in the region of the ankle. The feet are held in contact with the board, controlled oscillation of which is produced by an electrically driven crank mechanism. By suitable adjustment of the crank mechanism, the foot can be flexed through an angle of 0° about the vertical. However, this device is not intended for use while sitting and does not have structure for providing a pulsatile effect, e.g., to the patient's fluid filled channels.
McAlpine D A, Manohar C U, McCrady S K et al., “An office-place stepping device to promote workplace physical activity,” Br J Sports Med 2007; 41(12):903-907, describes stepping device that is easily movable, and can be housed under a desk and transported in a standard overnight case. The device has an accelerometer-containing, micro-electronic system that detects the motion of when the stepper is in use. The accelerometer is a tri-axial micro electro mechanical systems accelerometer that is equipped with USB functionality that enables the sensor to interface with a personal computer (PC) via a standard USB cable. The software then enables the user to monitor the use of the office-place stepping device from a PC. However, as with a treadmill desk discussed above, this device provides an active exercise of the user and hence requires multitasking, limiting the efficiency of work being done by the user.
Shimomura K, Murase N, Osada T et al., “A study of passive weight-bearing lower limb exercise effects on local muscles and whole body oxidative metabolism: a comparison with simulated horse riding, bicycle, and walking exercise,” Dyn Med 2009; 8:4, includes a description of a prototype machine to passively exercise the lower limbs. This equipment is composed of a saddle on which a subject sits, a rod to support the saddle, and two foot plates attached at the oblique front position to mount the feet. The saddle is adjustable for height so that the subject can do half-loaded exercise by keeping the flexion angle of the knee constant. The body weight of the subject was thus supported at three points by the saddle and both foot plates. The device induced motorized movements that moved the saddle repetitively in the front oblique direction.
In order to reduce pain associated with knee joint motion that might occur during exercise, the foot plates are designed to move downward in harmony with the support rod motion, which allows the subject to do exercise while maintaining the knee joint angle because the distance between the saddle and foot plates was constant. Repeated alternate right or left side shifts of the subject's center of gravity caused by oblique movements of the support rod imposed a larger amount of load on the lower limbs on the side of the slanted rod because the limbs were mobilized to regain body balance. The exercise intensity can be changed by varying the slant cycles. Intensities at 0.8, 1.2, and 1.6 Hz for 3 minutes each with a 5-minute rest between performances were studied. Passive weight-bearing lower limb exercise using this machine could provide approximately 3 MET of exercise and the thigh exhibited muscle activity equivalent to that of 80-watt bicycle or 6 km/hr walking exercise.
However, because of the extensive motion required, this machine cannot be used in an office environment and would require difficult multitasking in work related activities. In addition, the passive movement of this device is controlled by motorized rocking of the seat, and not the passive movement of the feet.
In view of the above, there is a need for a portable device that permits a user to achieve the benefits of application of pulsatile shear stress to the endothelium while still being able to perform other tasks, such as multi-tasking.